Antibody-drug conjugates on the up in cancer

Mylotarg served as a lesson of the pitfalls of ADCs: two years after it was pulled from the market some of the ADCs now in development will emerge as blockbusters

The first ADC to reach the market was Mylotarg (gemtuzumab ozogamicin) for acute myeloid leukaemia, which was developed by Wyeth (now Pfizer) and debuted in 2000. Ten years later, however, and the drug was taken off the market after its efficacy and safety came into question.

For the entire decade Mylotarg stood alone as the only ADC or 'magic bullet' on the market, which illustrates the difficulties besetting a field which has been challenging scientists ever since the technology to develop monoclonal antibodies was developed.

While a simple concept in principle – a cancer cell-targeting antibody is attached to a cytotoxic drug via some form of linker technology, allowing the payload to be selectively delivered to the tumour in preference to healthy cells – in practice there have been a number of obstacles.

Mylotarg provides an abject lesson on the pitfalls. The drug targeted a receptor (CD33) that turned out to be not as selective for tumour cells as once thought, while the linker used was unstable and allowed the cytotoxic component to be released early.

Lessons learned from the Mylotarg project and other ADC candidates have however allowed the magic bullet field to advance dramatically in recent years, according to Professor Christian Ottensmeier, professor experimental medicine at the University of Southampton in the UK.

“The magic has gotten better, and the bullets have gotten better,” says Ottensmeier, noting that a number of research strands have evolved in parallel in recent years.

“We are better at working out how to bind antibodies to reagents, and also at picking the right cellular targets for monoclonal antibodies.”

ADCs: taking the noise up a notchAfter Mylotarg's demise ADCs came to the fore again in 2011 when Seattle Genetics' CD30-targetting Adcetris (brentuximab vedotin, formerly SGN-35) was approved in the US to treat Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma. The drug pulled in $34.5m in the first quarter of 2012, and market watchers have predicted that peak sales could rise above $500m a year.

Then, at this year's American Society of Clinical Oncology (ASCO) meeting, the noise around ADCs went up another notch with the publication of interim phase III data on Roche/Genentech/Chugai's trastuzumab emtansine (T-DM1), which combines the anti-HER2 antibody used in blockbuster breast cancer treatment Herceptin (trastuzumab) with a cytotoxic drug licensed from ImmunoGen.

The EMILIA trial showed that T-DM1 significantly extended progression-free survival in HER2-positive metastatic breast cancer patients who had previously received treatment with Herceptin and taxane-based chemotherapy. That profile means it could bring in sales of more than $1.1bn at peak, according to analysts, well short of Herceptin's near-$6bn market but a major addition to the franchise.

“T-DM1 delivered in a way that made people stand up and take note,” says Ottensmeier, adding that the data “come at a time when the whole field of immunotherapy has woken up to the reality that ADCs are proper medicines”.

Monoclonal antibodies have demonstrated clear activity in cancer, but their curative potential is limited, says Ottensmeier.

“Herceptin makes a third of a third of breast cancer patients better for a little while, so there is a long way to go. If an ADC like T-DM1 can convert patients who no longer respond to Herceptin into patients who can benefit from therapy, these drugs will be used earlier and earlier in the treatment algorithm.”

Uptake could be even more profound if, as hoped, ADCs prove to have a lighter toxicological burden through their greater selectivity, although right now this is fairly speculative.

“Initially Rituxan targeting CD20 for B-cell malignancies and Herceptin for breast cancer were the only drugs that stood out among antibody-based cancer therapies … but now the number of licensed antibodies delivering specific immunological effects is enormous, and not just in cancer,” says Ottensmeier.

“I suspect the ADCs will follow a similar pattern,” he adds. “When you have a proof of principle that the medical community expects, development of new medicines tends to speed up.”

What is clear is that most of the big biopharma companies – that were arguably slow off the mark in developing antibody-only therapies – are throwing their weight behind ADCs, with the 3rd Annual World ADC Congress due to take place in San Francisco later this year featuring presentations from Pfizer, Bristol-Myers Squibb, Genentech, Amgen, Novartis, Astellas and Daiichi Sankyo, among many other smaller players.

Eight of the 20 cancer drugs in the clinic at Genentech are ADCs, for example, while Pfizer and BMS are both developing multiple candidates, albeit mainly in early stage trials.

And as might be expected, many of the ADCs in trials (see table) have tended to address lymphomas and other haematological malignancies where well-defined cellular targets mean there are already successful immunotherapy strategies in place.

“I'm sure that for solid tumours we're just at the tip of the iceberg,” says Ottensmeier, adding that one reason for the later stage of development is that – from an immunological perspective – researchers have focused on targets expressed inside the tumour cell rather than on its surface.

The ideal target sits on the surface but is being turned over and internalised. Such targets are starting to emerge for solid tumours, but identifying the best candidates will be the key limiting factor in the development of ADCs for non-haematological malignancies, he suggests.

While the early generation of ADCs are making their way through development, considerable research is ongoing on not only the cellular targets but also the cytotoxic payloads and the chelation chemistry used to link them to the antibody carriers.

Most drugs currently in development make use of the auristatins from Seattle Genetics or ImmunoGen's maytansine, but other classes are emerging – such as pyrrolobenzodiazepines in development at Spirogen – which may prove easier to combine with targeting antibodies. Wilex subsidiary Heidelberg Pharma is also among those looking at new payloads, with a series of ADCs in the pipeline based on a compound found in the death cap mushroom.

Evolving linkers used in ADCsThe linkers used in ADCs are evolving too, with other companies such as Syntarga and Mersana Therapeutics now coming forward with their own ADC toolboxes designed to make sure the cytotoxin stays firmly bound to the antibody until it is internalised into the cell.

Meanwhile, a related objective is to try to achieve greater uniformity of the ADC structure, for example though the use of site-specific conjugation. The trick is to build a sequence that encourages binding of the payload molecule to the antibody at a specific point, as the more generic the conjugation site, the more difficult it is to be accurate in terms of both the location and the number of cytotoxic groups attached.

“If you're delivering something that is exquisitely poisonous, then whether you have one, two or 10 payload molecules attached to the antibody will make a big difference in terms of predicting toxicity and establishing the correct dosing,” notes Ottensmeier. Companies working in this area include Ambrx, Redwood Bioscience and Sutro Biopharma.

Alternatives to monoclonal antibodiesAlternatives to conventional monoclonal antibodies are also being explored such as antibody fragments and alternative protein carriers, in light of the fact that for solid tumours very little of an antibody will actually penetrate into the cancer mass. That's one reason why the payloads carried by ADCs have to be so potent in the cell-killing activity.

Antibody fragments are physically smaller so can penetrate deeper tumours, so intuitively the makes sense, according to Ottensmeier. Another approach, pioneered by Anaphore, is trying the human plasma protein tetranectin as a delivery vehicle.

The size of the carrier may or may not be important, according to Ottensmeier. Antibody treatment of lymphomas is effective despite low penetration, for example, with high blood levels seemingly sufficient to effect a gradual 'whittling away' of the tumours. Moreover, there is evidence that smaller molecules tend to be cleared from the body more quickly.

The ADC field is currently akin to the early days of antibiotic therapy, according to Ottensmeier. “We still don't yet know how best to deploy these drugs. Should they be used on their own, alongside chemotherapy or with radiation treatment, for example? And should we treat people who have been treated successfully surgery, or only those with frank, visible disease?”

In time, some of the ADCs currently in development will emerge as blockbuster medicines in their own right, he predicted, and their fundamental role in cancer therapy will be assured.“

This really is the era of immunotherapy in its broadest sense, and to return once again to the antibiotics analogy, I believe in time we will have multiple classes of immunotherapeutics as we currently have multiple classes of antibiotics.”